Physiological regulation of the human growth hormone (GH)-insulin-like growth factor type I (IGF-I) axis: predominant impact of age, obesity, gonadal function, and sleep.

The growth hormone (GH)-insulin-like growth factor type I (IGF-I) axis is subject to exquisite regulation by multiple internal physiological variables and external cues. This review and update summarizes the impact of age, obesity, gonadal function and sleep on the control of GH secretion by the pituitary gland, as regulated by the dominant hypothalamic regulatory peptides, GH-releasing hormone (GHRH) and somatostatin. Available studies show an exponential decline in the calculated daily GH-secretion rate as a function of age in healthy men, such that every 7 years of advancing age beyond age 18-21 results in an approximately 50% decline. There are also strongly negative correlations between the daily GH-secretion rate and indices of obesity, such as the body mass index (BMI). For each increase in BMI of 1.5 kg/m2, there is a 50% decrease in the amount of GH secreted per day. At puberty, and across a span of adult ages, gonadal steroid-hormone concentrations in blood positively determine GH release. In particular, serum estradiol and testosterone concentrations are proportionate to GH-secretory burst mass and mean serum GH concentrations. Deep sleep (stages 3 and 4) is accompanied by markedly increased pulsatile GH secretion that can be accounted for mechanistically by presumptive somatostatin withdrawal combined with hypothalamic GHRH release. Lastly, body composition (especially visceral adiposity) appears to be a dominant negative determinant of GH production, since the relationships between GH secretion and age, testosterone, or sleep are all attenuated or abolished by adiposity. Recent data using pulsatile GHRH treatment or pharmacological methods to reduce somatostatin secretion point to combined defects in GHRH release and somatostatin excess as the most plausible pathophysiology of hyposomatotropism accompanying obesity.